Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.
Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.
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DOI：
10.1038/s41467-021-24524-8
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发表时间：
2021-07-12
影响因子：
16.6
通讯作者：
Bankiewicz KS
中科院分区：
文献类型：
--
作者：
Pearson TS;Gupta N;San Sebastian W;Imamura-Ching J;Viehoever A;Grijalvo-Perez A;Fay AJ;Seth N;Lundy SM;Seo Y;Pampaloni M;Hyland K;Smith E;de Oliveira Barbosa G;Heathcock JC;Minnema A;Lonser R;Elder JB;Leonard J;Larson P;Bankiewicz KS
芳香族L-氨基酸脱羧酶（AADC）缺乏症是一种罕见的遗传性疾病，其特征是多巴胺和5-羟色胺合成不足。它出现在婴儿早期，并导致严重的发育障碍和终身运动，行为和自主神经症状，包括眼球转动危机（OGC），睡眠障碍和情绪障碍。我们研究了将表达AADC的病毒载体（AAV 2-hAADC）递送至患有AADC缺陷的儿童的中脑的安全性和有效性（ClinicalTrials.gov Identifier NCT 02852213）。7名4-9岁的儿童在2个剂量组中接受AAV 2-hAADC向双侧黑质（SN）和腹侧被盖区（VTA）的对流增强递送（CED）（总输注体积：每个半球80 μL）：1.3 × 1011 vg（n = 3）和4.2 × 1011 vg（n = 4）。主要目的是证明手术的安全性，并记录脑AADC活性恢复的生物标志物证据。次要目的是评估症状和运动功能的临床改善。直接双侧输注AAV 2-hAADC是安全的，耐受性良好，并且分别实现了SN和VTA的98%和70%的目标覆盖。所有受试者的多巴胺代谢增加，中脑和纹状体内FDOPA摄取增强。术后第3个月，7例受试者中有6例OGC完全消退。术后12个月，6/7例受试者获得了正常的头部控制，4/7例可独立坐立。在18个月时，2例受试者可以在双手支撑下行走。达到了研究的主要和次要终点。AADC缺陷儿童的中脑基因递送是可行和安全的，并导致症状和运动功能的临床改善。芳香族L-氨基酸脱羧酶缺乏症（AADC）是一种罕见的神经发育障碍。在此，作者描述了MR引导下递送AAV 2-AADC治疗AADC的临床试验。
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function. Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.
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影响因子：
9.9
作者：
Brun, L.;Ngu, L. H.;Blau, N.
通讯作者：
Blau, N.
影响因子：
--
作者：
Sehara, Yoshihide;Fujimoto, Ken-ichi;Muramatsu, Shin-ichi
通讯作者：
Muramatsu, Shin-ichi
影响因子：
12.4
作者：
Muramatsu, Shin-ichi;Fujimoto, Ken-ichi;Nakano, Imaharu
通讯作者：
Nakano, Imaharu
影响因子：
11.2
作者：
Kordower, Jeffrey H.;Herzog, Christopher D.;Bartus, Raymond T.
通讯作者：
Bartus, Raymond T.
DOI：
10.1007/8904_2017_54
发表时间：
2018-01-01
期刊：
JIMD REPORTS, VOL 40
影响因子：
--
作者：
Hwu, Wuh-Liang;Chien, Yin-Hsiu;Li, Mei-Hsin
通讯作者：
Li, Mei-Hsin